Clonal hematopoiesis in survivors of childhood cancer.
Authors: Danielle Novetsky Friedman, Irenaeus Chi-Chung Chan, Chaya S. Moskowitz, Shanita Li, Kimberly Turner, Jie Liu, Nancy Bouvier, Michael Francis Walsh, Barbara Spitzer, Andrew Kung, Michael F. Berger, Megan A. Cooper, Iskra Pusic, Geoffrey L. Uy, Daniel C Link, Todd E Druley, Luis A. Diaz, Ross L. Levine, Neerav Shukla, KELLY L BOLTON
Journal: Journal of Clinical Oncology (2023)

10014 Background: Subsequent malignancies and cardiovascular (CV) disease are the leading cause of premature death in childhood cancer survivors, a population also at risk for premature aging. Clonal hematopoiesis (CH), the age-related clonal expansion of mutated hematopoietic stem cells, is a prominent risk factor for early-onset malignant and CV disease. Data are lacking on the prevalence of CH in childhood cancer survivors. Methods: We evaluated the prevalence of CH in a retrospective case-control study of childhood cancer survivors and matched controls (all ≥13 years of age). Cases included individuals diagnosed with a solid tumor or lymphoma at age ≤25 years who were ≥6-months from completion of chemotherapy and/or radiotherapy. Age-matched controls (5-year age bins) with and without a history of cancer were included, given evidence of shared genomic risk factors between cancer and CH. Samples were batched and sequenced at an average depth of 19,830x using a custom, targeted amplicon-based UMI sequencing platform (ArcherDX), which included full exons of DMNT3A, TET2, ASXL1, TP53, CHEK2 and targeted regions of PPM1D, SRSF2, SF3B1, JAK2. Mutations at a variant allelic frequency (VAF) ≥ 0.02% were identified with VAF &gt; 2% considered clinically significant. Logistic regression adjusted for age, gender, and race was used to test for an association between CH and case-control status. Results: Samples were analyzed from 104 childhood cancer survivors (median age 19 years [y], range, 13-49y; median time since end-of-therapy: 10y, range 0.5-39y), 71 controls with untreated, newly diagnosed cancer (median age 25y, range 8-48y), and 68 healthy controls (median age 23y, range, 15-51y). The frequency of CH was higher in childhood cancer survivors compared to controls across ages with CH detected in 36.5% of survivors and 20.1% of controls (OR 3.2, 95% CI, 1.6-6.1). The enrichment of CH in survivors was observed both relative to healthy controls (OR 2.3, 95% CI 1.1-5.3) and treatment-naïve solid tumor controls (OR 5.0, 95% CI, 2.1-13.7). A trend toward a stronger association for CH mutations with VAF &gt; 2% (OR 10.9, 95% CI, 1.9-60.7) compared to VAF &lt; 2% (OR 2.7, 95% CI, 1.4-5.2) was observed. The most commonly mutated genes were in the DTA ( DNMT3A, TET2 and ASXL1) and DDR ( PPM1D, TP53 and CHEK2) classes. While a higher proportion of both DTA and DDR mutations was noted among survivors compared to controls, the enrichment of DDR mutations was stronger than DTA (OR 7.1, 95% CI 2.8-18.3 for DDR; OR 2.3, 95% CI 1.1-4.6 for DTA). A sub-analysis of 5 year survivors showed a higher frequency of CH in this cohort compared to controls (OR 2.8, 95% CI, 1.3-5.9). Conclusions: Childhood cancer survivors have higher frequencies of CH than age-matched controls, which persists for years after treatment. These data suggest that CH may, in part, drive the long-term premature multimorbidity seen in survivors. Longitudinal assessment of CH among survivors may be indicated to elucidate these associations.